This objective of this proposal is to characterize the behavioral and neural substrates that determine individual differences in the efficacy of morphine as a reinforcer and vulnerability to opioid-reinforced behavior. The specific hypothesis to be tested is that a significant relationship exists between individual differences in mesolimbic mu-opiate receptor concentration and the efficacy of morphine as a primary reinforcer. The projects outlined in this proposal will utilize genetically engineered animal models with behavior genetic and neuroanatomical techniques to investigate the relationship between regional mu-opiate receptor concentration and morphine-reinforced behavior. Inherited differences in regional mu-opiate receptor concentration (genetically engineered and naturally occurring) will be used as the independent variable to determine if differences in the distribution of mu-opiate receptors within the mesolimbic system significantly affect the efficacy of morphine as a reinforcer. Intravenous morphine self-administration behavior will be investigated in two sets of genetically engineered mice that overexpress the mu-opiate receptor, two commonly used recombinant inbred strains with high and low opiate receptor concentration and the two parental inbred strains used for transgenic animal production. Central mu-opiate receptor distribution in all genotypes will be characterized via autoradiographic techniques. Multivariate analysis of the relationship between mu-opiate receptor concentration in specific neuroanatomical regions and self- administration behavior will determine if a particular region or combination of regions accounts for the genetic variance seen in self- administration behavior. Overall, these projects will directly test the effect of genetically engineered alterations in CNS opiate-receptor concentration on the reinforcing effects of intravenous morphine injections and test the hypothesis that mu-opiate receptor concentration in one or more regions of the mesolimbic system are predictive of genotype-dependent differences in morphine self-administration behavior. if the results of the multivariate analysis identify a region or combination of regions that account for a significant portion of the variance seen in self-administration behavior, these results will provide a significant step towards identifying specific neural regions involved in the neurobiological substrates underlying vulnerability to opioid addiction.